Overlapping cistrons in a family of ion channel genes

离子通道基因家族中的重叠顺反子

• 批准号: 9007668
• 负责人: Christopher Manuel Gomez
• 金额: $ 44.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9007668
• 关键词: Affinity Chromatography; Autistic Disorder; Behavioral; Binding; Binding Proteins; Biology; C-terminal; Calcium Channel; Cistrons; Code; Complex; Connexins; DNA; Development; Disease; Electrophoretic Mobility Shift Assay; Embryo; Eukaryota; Eukaryotic Initiation Factors; Family; Family member; Gel Chromatography; Gene Deletion; Gene Expression; Gene Family; Gene Targeting; Genes; Genetic; Glutamine; Goals; Hereditary Disease; Heterozygote; Human Genetics; Immunohistochemistry; In Vitro; Incubated; Internal Ribosome Entry Site; Ion Channel; Lead; Longevity; Luciferases; Mass Spectrum Analysis; Mediating; Messenger RNA; MicroRNAs; Mutation; Nature; Nuclear; Open Reading Frames; P-Q type voltage-dependent calcium channel; Pathogenesis; Peptide Initiation Factors; Phenotype; Play; Precipitation; Prevalence; Property; Proteins; Purkinje Cells; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Relative (related person); Reporter; Role; Schizophrenia; Series; Site; Structure; Trans-Activators; Transcript; Transgenic Mice; Transgenic Organisms; Translating; Translations; Type 6 Spinocerebellar Ataxia; Vertebrates; Western Blotting; chromatin immunoprecipitation; crosslink; developmental disease; genetic regulatory protein; loss of function; member; multitask; nerve supply; nervous system disorder; neurobehavioral disorder; neuropsychiatry; notch protein; novel; pleiotropism; polypeptide; protein complex; public health relevance; therapeutic target; therapy development; transcription factor; transcriptome sequencing; voltage

 DESCRIPTION (provided by applicant): We have discovered that the CACNA1A gene, which encodes the P/Q type voltage gated calcium channel (VGCC) is bicistronic. The CACNA1A mRNA encodes both the a1A subunit and a second protein, a1ACT, a transcription factor, that is translated as a second open reading frame due to a cryptic internal ribosomal entry site (IRES). Simultaneous expression of two proteins in the same cellular mRNA, one of which is a transcription factor, may be a powerful strategy used by calcium channels and other cellular genes to coordinate expression of an ensemble of genes. To understand this new class of IRES and bicistronic genes we will: 1. Determine how the CACNA1A IRES is regulated by RNA-binding proteins and miRNAs; 2. Define the novel properties of bicistronic genes of the VGCC family. 3. Determine whether altered bicistronic gene expression leads to the complex phenotypes of VGCC disorders. This study will help us to understand the biology of bicistronic cellular genes in particular among other VGCCs, the nature of the IRES regulatory mechanisms and proteins they encode, and the possible role in the pathogenesis and treatment of complex human genetic disease.

 描述（申请人提供）：我们发现编码P/Q型电压门控钙通道（VGCC）的CACNA1A基因是双顺反子的。 CACNA1A mRNA 编码 a1A 亚基和第二种蛋白质 a1ACT（一种转录因子），由于隐藏的内部核糖体进入位点 (IRES)，它被翻译为第二个开放阅读框。在同一细胞 mRNA 中同时表达两种蛋白质（其中一种是转录因子）可能是钙通道和其他细胞基因用来协调基因组表达的强大策略。为了了解这一类新的 IRES 和双顺反子基因，我们将： 1. 确定 CACNA1A IRES 如何受到 RNA 结合蛋白和 miRNA 的调节； 2. 定义VGCC家族双顺反子基因的新特性。 3. 确定双顺反子基因表达的改变是否会导致 VGCC 疾病的复杂表型。这项研究将帮助我们了解双顺反子细胞基因的生物学，特别是其他 VGCC 中的双顺反子细胞基因、IRES 调节机制及其编码蛋白质的性质，以及在复杂人类遗传疾病的发病机制和治疗中的可能作用。